Cigarette smoking is a major contributing factor for the development of cardiovascular diseased including atherosclerosis. It induces also a hightly complex pharmacological action, primarily because each smoker inhales with the smoke aerosol more than 3,800 compounds many times each day. Several of these compounds have been associated with accelerated atherogenesis, but as yet, demonstration of disease similar to that seen in humans has not been verified in animals in response to individual smoke constitutents, or to the total inhaled smoke. It is the aim of this proposal to initiate such an investigation and to identify fractions of tobacco smoke which might exert atherogenic effects on the arterial wall. We will extend and characterize our preliminary observations (included herein) on the development of atherosclerosis in Syrian golden hamsters exposed to mainstream smoke for 18 months. Specifically, through histological, morphological and biochemical methods, we proposed to analyze aortic tissue derived from controls and from animals exposed to smoke fractions, as well as total mainstream smoke, and to determine the extent of plaque formation in response to the isolated risk factor of cigarette smoking. Increased atheroscherosis has been demonstrated at autopsy in human cigarette smokers, but assignment of relative risk can be made only with animal bioassays where cause and effect relationships can be tested. We will conduct our studies in Syrian golden hamsters, a well established animal model for smoke exposure. They are tolerant of the smoking regimes, have circulating lipid levels similar to humans and respond to tobacco-specific carcinogens. In addition, our preliminary results demonstrate that these animals develop biochemical markers of atherosclerosis during long-term exposure to mainstream cigarette smoke. The fractions present in cigarette smoke which exert atherogenic effects remain to be elucidated. With consideration of the changing cigarette product, this research is essential in determining relative risks of various cigarette yields and for developing concepts for reducing cardiovascular risks.